This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Based on laboratory studies and our understanding of their mechanism of action, there will be a profound positive interaction between two oral drugs approved for the treatment of neuropathic pain (gabapentin and duloxetine) and an oral drug approved for treatment of dementia (donepezil) to treat patients with chronic pain. This study is in patients with neuropathic pain, and will culminate in a quantitative description of interactions between activators of descending noradrenergic activity, norepinephrine transporter inhibitors, and cholinesterase inhibitors to exploit this unique plasticity of analgesia in chronic pain states. We focus not only on mechanistic hypotheses in the laboratory studies, but also on practical applications, using clinically approved drugs, including gabapentin (Neurontin[unreadable]) to activate noradrenergic activity, duloxetine (Cymbalta[unreadable]) to inhibit the norepinephrine transporter, and donepezil (Aricept[unreadable]), approved for the treatment of Alzheimer s dementia, but not previously tested to treat neuropathic pain, to inhibit cholinesterase. Each of these drugs may act by mechanisms in addition to those involved in descending noradrenergic inhibition, but we hypothesize that the therapeutic strength of their combination relies heavily on this cascade engendered by noradrenergic sprouting and altered a2-adrenoceptor function. The proposed study will provide critical tests of this hypothesis and critical information to guide more effective clinical therapy of neuropathic pain.